The prevalence of airway diseases has increased in recent decades despite therapeutic advances. Among the airway diseases, asthma exacerbations and chronic obstructive pulmonary disease (COPD) are major causes of hospitalization. Both asthma and COPD involve chronic inflammation of the respiratory tract. Despite the presentation of similar symptoms, such as dyspnea, coughing, wheezing and expectoration, these airway diseases have different underlying pathophysiological processes. COPD is a term which refers to a large group of lung diseases characterized by obstruction of air flow that interferes with normal breathing. Emphysema and chronic bronchitis are the most important conditions that compose COPD (COPD—Chronic Bronchitis & Emphysema; Australian lung foundation, 2006). COPD involves chronic inflammation of the peripheral airways and lung parenchyma, which leads to progressive narrowing of the airways and shortness of breath. On the other hand Asthma is characterized by episodic airway obstruction and symptoms and usually starts early in life. The inflammation differs markedly between asthma and COPD, with different cells, mediators, consequences and, there is a difference in response to corticosteroids (Clinics (Sao Paulo). 2012; 67(11):1335-43). However, more recently it has become clear that severe asthma is much more similar to COPD, with similarities in the inflammation and sharing a poor response to corticosteroids (J Allergy Clin Immunol. 2013; 131(3):636-45). Interestingly, studies of molecular genetics are now showing that severe asthma and COPD share several gene polymorphisms (Comp Funct Genomics. 2012; 2012: 968267).
Chronic obstructive pulmonary disease (COPD) is a major global health problem that is becoming prevalent, particularly in developing countries. It is one of the most common diseases in the world, with a lifetime risk estimated to be as high as 25%, and now equally affects both men and women (Nature Reviews 2013; 12: 543-559)
Current forms of therapy for COPD are relatively ineffective, as there are no drugs available that considerably reduce disease progression or mortality or have a substantial effect on exacerbations, which are one of the most common causes of hospital admissions.
Long acting bronchodilators are the mainstay of current COPD therapy. There have been several advances in the development of β2-adrenergic receptor agonists and muscarinic receptor antagonists that only need to be administered once a day. Moreover, long acting β2-adrenergic receptor agonists (LABAs) and long-acting muscarinic acetylcholine receptor antagonists (LAMAs) have additive effects on bronchodilation and in the improvement of symptoms, which has led to the development of LABA-LAMA combination inhalers. However, although these drugs produce effective bronchodilation, they fail to treat the underlying inflammatory disease in patients with COPD.
Alternatively or additional to bronchodilators, oral or inhaled corticosteroids could also be used as COPD therapy. But corticosteroids have limitations as long term oral corticosteroid therapy is not recommended and inhaled corticosteroids are known to be associated with increased risk of pneumonia in patients. (www.bcguidelines.ca) Moreover, Inhaled corticosteroids are found largely ineffective in significant number of COPD patients as an anti-inflammatory therapy in COPD (Ann Fam Med. 2006; 4(3):253-62). Phosphodiesterase inhibitors (PDE-4 inhibitors) have recently been shown to document clinical efficacy in COPD, although their utility is hampered by class related side effects. (International Journal of COPD 2007; 2(2): 121-129)
With better understanding of the pathophysiology of COPD disease process and recognition of inflammation as an important feature, it is anticipated that disease modifying therapy for COPD targeting underlying inflammation will prove effective the way it has been successful in the treatment of other chronic inflammatory conditions like RA.
Many kinases are involved in the regulation of proinflammatory transcription factors and inflammatory genes. The mitogen-activated protein kinase (MAPK) family includes the p38 kinases, which consists of highly conserved proline-directed serine-threonine protein kinases that are activated in response to inflammatory signals. The p38 MAPK pathway, which is activated by cellular stress, regulates the expression of many inflammatory genes that are involved in COPD (Nature Reviews 2013; 12: 543-559). Proinflammatory cytokines/chemokines and environmental stress activates p38 mitogen activated protein kinase (MAPK) by phosphorylation, which in turn activates p38 MAPK signaling pathway. p38 is involved in the inflammatory responses induced by different stimuli through activation and release of proinflammatory cytokines/chemokines, posttranslational regulation of these genes, and activation of inflammatory cell migration. Therefore, p38 inhibitors present a potentially attractive treatment target for the chronic inflammatory conditions including COPD. Of the four isoforms known so far, p38 alpha is the most abundant in inflammatory cells and has been the most studied.
Over the past two decades, p38 MAPK (mitogen-activated protein kinase) has been the subject of intense multidisciplinary research. p38 MAPK inhibitors have been shown to be efficacious in several disease models, including rheumatoid arthritis, psoriasis, Crohn's disease, and stroke. Recent studies support a role for p38 MAPK in the development, maintenance, and/or exacerbation of a number of pulmonary diseases, such as asthma, cystic fibrosis, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. There is now an abundant literature which demonstrates that p38 MAPK is activated in chronic inflammatory conditions and that its activation results in the elaboration and release of further proinflammatory cytokines (Expert Opin. Investig. Drugs 2008; 17(10):1411-1425).
Though orally administered small molecule inhibitors targeted to P38 MAPK have proved to be effective in reducing various parameters of inflammation in cells and tissues obtained from patients with COPD in initial clinical studies, the major obstacle hindering the definition and exploitation of the potential utilities of p38 MAPK inhibitors in the treatment of human chronic inflammatory diseases has been the toxicity observed in patients. This has been sufficiently severe to result in the withdrawal from clinical development of many of the compounds progressed. Presently, none of them is yet approved anywhere in the world because one or the other problems associated with selected molecules such as toxicity or selectivity (Expert Opin. Investig. Drugs 2008; 17(10):1411-1425 & Chest 2011; 139(6): 1470-1479).
For example, pyridinyl imidazole based p38 MAPK inhibitors into clinical trials were found to be associated with unacceptable safety profile. The side effects reported both preclinically and clinically for other similar p38 MAPK inhibitors include hepatotoxicity, cardiotoxicity, light headedness and other CNS toxicities, skin rash, gastrointestinal tract symptoms, and infections. Some question of selectivity has also arisen for these molecules. Similarly, BIRB-796, a noncompetitive p38 MAPK inhibitor for ATP was evaluated for its activity but it has been withdrawn from Phase II clinical trials for rheumatoid arthritis, possibly because of liver enzyme elevations. (Expert Opin. Investig. Drugs 2008; 17(10):1411-1425 & Chest 2011; 139(6): 1470-1479).
A Phase II study with another p38 MAPK inhibitor Vx-745, in rheumatoid arthritis patients displayed significant clinical benefit compared to placebo at the single low dose tested. However, it was also discontinued because of undisclosed CNS toxicity in dogs during a 6-month safety study. (Expert Opin. Investig. Drugs 2008; 17(10): 1411-1425)
To overcome these problems of toxicity and selectivity of the target associated with known p38 MAPK inhibitors, some alternative strategies were designed. One of them was to design the treatment approaches wherein p38 kinase inhibitor is dosed directly to the inflamed organ.
Other strategies include developing newer generation p38 MAPK inhibitors with improved selectivity and lesser side effect profile. For example, PH-797804 and Losmapimod have been shown to be well tolerated in clinical studies when treated up to 12-24 weeks. (Thorax. 2013 August; 68(8): 738-45 & J Clin Pharmacol. 2012 March; 52(3): 416-24)
There remains a need to identify and develop new p38 MAPK inhibitors which provides desired therapeutic potential along with improved pharmacokinetic profile and/or lesser side effects.
WO200214321 discloses polycyclic imidazole derivatives as STAT-6 inhibitors for the treatment of cancer or to sensitize cancer cells to other anti-cancer treatment.
GB2232666 and GB2211186 disclose imidazobenzothiazoles as benzodiazepine inverse agonist for the treatment of memory problem, obesity or can be used as minor tranquilizers.
Present invention provides novel fused imidazobenzothiazole derivatives as p38 MAPK inhibitors, which have demonstrated desired efficacy and safety profile.